The present invention relates to the preparation of hydroxythiol compounds, and, more specifically, to the preparation of isomerically pure hydroxythiophenols. In particular, the present invention relates to a commercially feasible hydroxythiophenol synthesis in which significant quantities of the isomerically pure reaction product are obtained.
General methods for the preparation of thiol compounds using the Grignard-sulfur reaction are known in the literature. Halide compounds are reacted with magnesium metal and then sulfur powder to produce a thiol. The extension of the Grignard reaction to hydroxy halide compounds requires protection of the reactive hydroxyl group. However, even when hydroxyl group protection is employed, low yields are obtained.
Isomerically pure hydroxythiophenols are important reagents and starting materials for a variety of pharmaceutical, agrochemical and chemical processes. 3-Hydroxythiophenol, in particular, has been used as a key starting material for the synthesis of a new drug for the prevention of breast cancer. The commercial demands for these compounds have created a need for their practical large scale production.
Diazonium salt reactions are generally employed to substitute a phenyl ring with a hydroxyl group. An isomerically pure hydroxythiophenol could thus be prepared by reacting an isomerically pure aminothiophenol with NaNO2 and H2SO4 to form the corresponding diazonium salt, which could then be converted to a hydroxythiophenol by reaction with water.
The diazonium salt reaction with aminothiophenol, however, produces a poor yield of diazonium salt. Furthermore, aminothiophenols are sulfur-containing nucleophiles that tend to react violently with diazonium reagents. General methods for the preparation of thiophenols using the aryl Grignard-sulfur reaction are known in the literature, but, consistent with other hydroxy halide compounds, low yields are obtained. There remains a need for a commercially practical method of producing hydroxythiophenols in high yield.
This need is met by the present invention. It has now been discovered that the Grignard-sulfur reaction produces poor yields of hydroxythiol compounds because the well-known hydroxyl protecting groups typically employed with Grignard reactions form species upon de-protection that attack thiol groups. This is particularly a problem in the preparation on hydroxythiophenols. Therefore, significant quantities of isomerically pure hydroxythiol compounds may be produced by means of the Grignard-sulfur reaction if the species formed upon de-protection of the hydroxyl group is removed from the reaction mixture before it reacts with the newly-formed thiol group, or if a hydroxyl protecting group is employed that upon de-protection forms species that are inert toward thiol groups.
The present invention incorporates the discovery that previous attempts to synthesize hydroxythiol compounds using an Grignard-sulfur reaction were unsuccessful because of the protecting groups employed. For example, the commonly-used tetrahydropyranyl protecting group, formed dihydropyran upon de-protection, which attacked the newly-formed thiol group. By either using a hydroxyl protecting group that upon de-protection forms a species that is inert toward the thiol group, or that is removed from the reaction mixture before it reacts with the newly-formed thiol group, isomerically pure hydroxythiol compounds are produced in commercially useful yields.
The present invention thus provides an improved method for the preparation of hydroxythiol compounds in which, as shown in Step I, a hydroxyl-protected halogenated compound is reacted with magnesium in a Grignard-suitable solvent to form a hydroxyl-protected magnesium halide compound:
Step I 
The magnesium halide is then reacted with sulfur in the Grignard-suitable solvent, as shown in Step II, to form a hydroxyl-protected, thiomagnesium halide, which may contain some di- and polysulfide species:
Step II 
According to one embodiment of the method of the present invention, the hydroxyl protecting group is selected so that upon de-protection the species that are formed by the protecting group are inert toward thiols. In this aspect of the method of the present invention, the hydroxyl group may be hydrolyzed and de-protected, before the thiomagnesium halide is converted to the thiol.
According to another embodiment of the method of the present invention, when the hydroxyl group is de-protected, the species that is formed is removed from the reaction mixture before it reacts with the newly-formed thiol group.
In both embodiments, the reaction mixture is then treated with a reducing agent (to reduce the di- and polysulfide species that form). This increases the reaction yield. The de-protection, thiol conversion and reduction is shown in Step III:
Step III 
Because the reaction itself does not generate isomers, the method of the present invention is useful for the synthesis of isomerically pure regio-isomeric hydroxythiol compounds, and particularly useful for the synthesis of isomerically pure hydroxythiophenol compounds. Hydroxythiophenol synthesis is depicted in Steps I-III when R is an unsubstituted or substituted phenyl group.
For purposes of the present invention, an xe2x80x9cisomerically purexe2x80x9d reaction product contains the same level of isomeric impurities as its starting material. Therefore, with the method of the present invention, the isomeric purity of the reaction product will depend upon the isomeric purity of its starting material, and it is possible to obtain an isomeric purity of 95 wt % and greater.
Thus, to obtain an isomerically pure end product, an isomerically pure starting material must be employed. Such materials are also commercially available or may be prepared by known methods. Isomerically pure halogenated phenols and alkylphenols, when not available commercially, are prepared using well-known halogenation reactions that are essentially conventional. Suitable reagents, solvents and process conditions may be determined by reference to March, J., Advanced Organic Chemistry (2nd Ed., McGraw-Hill, 1977), (the disclosure of which is incorporated herein by reference) and through routine optimization of reaction parameters. The alkyl and aryl halide isomers that form have distinct boiling points and are separated on a commercial scale by distillation.
Another aspect of the present invention, provides intermediate compounds having the structure of Formula I: 
Y is selected from straight-chained or branched, unsubstituted or substituted C1-C20 alkyl, aryl, aralkyl, tertiary amino, amido and alkoxyl groups; n is between 0 and 4, inclusive; Pg is a protecting group that upon de-protection forms a species that is inert toward thiols; and X is selected from SH, Z, MgZ and SMgZ, wherein Z is selected from F, Cl, Br and I.
The method of the present invention utilizes halogenated hydroxyl compounds as starting materials. The compounds are commercially available. Alternately, they may be prepared using the conventional techniques described above. The hydroxyl group is protected with a suitable protecting group, to provide a compound having the structure of Formula II:
Xxe2x80x94Rxe2x80x94OPg xe2x80x83xe2x80x83(II)
wherein X and Pg are as described above for Formula I and R is a substituted or unsubstituted aliphatic radical, a substituted or unsubstituted cyclic aliphatic radical, a substituted or unsubstituted aromatic radical, a substituted or unsubstituted araliphatic radical or a substituted or unsubstituted heterocyclic radical.
More preferably, R is a substituted or unsubstituted, straight-chained or branched C1-C20 alkyl radical, a substituted or unsubstitued C3-C10 cycloalkyl radical, a substituted or unsubstituted C6-C15 aryl radical, a substituted or unsubstituted C7-C13 aralkyl radical, or a substituted or unsubstituted 3-6 member heterocyclic radical. Essentially any substitution group that is inert toward Grignard reagents or is capable of being protected from reaction with Grignard reagents may be employed. Suitable substitution groups, substitution groups requiring protecting groups, protecting groups and methods of protection are well-known. Pg may be used as a protecting group. Examples of substitution groups include C1-C6 aliphatics such as alkyls, alkoxys and alkenyls, C6-C15 aryls, C3-C8 cyclic aliphatics, tertiary aminos and amidos. The substitution groups may be straight-chained or branched and substituted or unsubstituted, as well.
R as a C1-C20 alkyl radical may be, for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, or 2-ethylhexyl radical. Any of these groups may be substituted with methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or methanesulphonyl, to form, for example, methoxymethyl, 2-methoxyethyl, 2-ethoxymethy, n-butoxyethyl, 3-methoxypropyl, 1-methoxybutyl, 2-methoxybutyl, methanesulphonylmethyl or 2-methanesulphonylethyl. In a preferred class of alkyl radicals, R is a straight chain C2-C6 alkyl radical, especially a ethyl or butyl radical.
R as a C3-C10 cycloalkyl radical may be, for example, a cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopentyl, cylcohexyl, methylcyclohexyl dimethylcyclohexyl, cycloheptyl, or cyclooctyl radical. Any of these groups may be substituted by methoxy, ethoxy, n-propoxy, isopropoxy or n-butoxy. In a preferred class of cycloalkyl radical, R is a C6-C8 cycloalkyl radical, even more preferably, a dimethylcyclohexyl radical.
R as a 3-6 ring member heterocyclic radical may include known heterocyclic atoms such as N, O and S. Suitable heterocycles include, for example, pyran, thiophene, pyrrole, furan, pyridine, or derivatives thereof
R as a C6-C15 aryl may be, for example, phenyl, o-tolyl, m-tolyl, p-tolyl, o-xylyl, m-xylyl, p-xylyl, alpha-naphthyl or beta-naphthyl. Any of these groups may be substituted, for example, with C1-C14 alkyl, aryl, aralkyl, amino (primary, secondary or tertiary), amido, alkoxyl or hydroxyl. In a preferred class of compounds, R is C6-C12 aryl, especially phenyl or naphthyl.
R as a C7-C20 aralkyl radical may be, for example, benzyl, 4-methylbenzyl, o-methylbenzyl, p-methylbenzyl, diphenylmethyl, 2-phenylethyl, 2-phenylpropyl or 3-phenylpropyl, and preferably a C7-C9 aralkyl, especially benzyl. Any of these groups may also be substituted, for example, with C1-C14 aryl, aralkyl, tertiary amino, amido or alkoxyl groups.
In a still more preferred embodiment, R is a aryl or aralkyl radical, so that the compound of Formula II is a hydroxyl-protected aryl halide. The compound is formed by protecting the hydroxyl group of a halogenated phenol or alkylphenol by conventional methods.
Examples of suitable protecting groups for Pg include silyl groups such as trialkyl-silyls, including trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, C1-C10, alkyl and substituted alkyl groups may also be employed, including methyl and substituted methyl groups, such as methoxymethyl, t-butyl, dihydropyranyl groups; ethyl and substituted ethyl groups such as 1-ethoxyethyl, 1-methyl-1-methoxyethyl, and C6-C20 aryl and substituted aryl groups, and C7-C20 aralkyl and substituted aralkyl groups, such as benzyl and substituted benzyl groups, such as p-methoxybenzyl, and p-phenylbenzyl groups. 2-(Trimethylsilyl)ethoxymethyl (SEM) may also be used, which is an alkylsilyl, as well as a substituted methyl, protecting group.
Hydroxyl protecting groups that upon de-protection form protecting group species that are inert toward thiophenols include alkylsilyl groups, such as the aforementioned silyl protecting groups, SEM, and groups that form unreactive alcohols upon de-protection, including alkyl, aryl, aralkyl, alkoxy, aryloxy and arylalkoxy groups. Protecting groups that upon de-protection form species that are reactive toward thiophenols include groups that form species that are reactive with sulfur-containing nucleophiles, such as tetrahydropyran and t-butyl protecting groups.
When the aryl or aralkyl group of R is a phenyl or alkylphenyl group the compound of Formula II is an intermediate compound of Formula I in which X is F, Cl, Br or I and Y and n are as described above for Formula I. When n is zero, the compound of Formula I corresponds to the compound of Formula II in which R is an unsubstituted phenyl group, and when n is one or two, the compound of Formula I corresponds to the compound of Formula II in which R is a substituted phenyl or alkylphenyl group. Accordingly, Y of Formula I represents the groups with which the aryl and aralkyl groups of Formula I may be substituted, i.e., for example, straight-chained or branched, substituted or unsubstituted C1-C20 alkyl, aryl, aralkyl, tertiary amino amido or alkoxyl.
The hydroxyl-protected halide compound is then allowed to undergo the Grignard reaction of Step I using magnesium in a conventional Grignard-suitable solvent. This reaction step is essentially conventional, and suitable reagents, solvents and process conditions may be determined by reference to the above cited March, J., Advanced Organic Chemistry (the disclosure of which is incorporated herein by reference) and by routine optimization of reaction parameters. Typically, an ether is employed as a Grignard solvent. Examples of suitable ethers include tetrahydrofuran (THF), diethyl ether, isopropyl ether and methyl tert-butyl ether (MTBE).
A magnesium halide compound is obtained having the structure of Formula II, in which R and Pg are as described above with respect to Formula II and X is selected from MgF, MgCl, MgBr and MgI. When R is a phenyl or alkylphenyl group, the compound of Formula II is an intermediate compound of Formula I in which X is MgF, MgCl, MgBr or Mgl and Y and n are as described above for Formula I. When n is greater than zero, Y of Formula I again represents the groups with which the aryl and aralkyl R groups of Formula II may be substituted.
The magnesium halide compound is reacted as depicted in Step II with elemental sulfur suspended in a dry Grignard-suitable solvent under an inert atmosphere such as nitrogen.
This reaction step is also essentially conventional, and suitable reagents, solvents and process conditions may be determined by reference to the above-cited Advanced Organic Chemistry and by routine optimization of reaction parameters.
A thiomagnesium halide compound is thus obtained, having the structure of Formula II, in which R and Pg are as described above with respect to Formula II and X is selected from SMgF, SMgCl, SMgBr and SMgI. When R is a phenyl or alkylphenyl group, the compound of Formula II is an intermediate compounds of Formula I in which X is SMgF, SMgCl, SMgBr or SMgI and Y and n are as described above for Formula I. When n is greater than zero, Y again represents the groups with which the aryl and aralkyl R groups of Formula II may be substituted.
As depicted in Step III, the thiomagnesium halide compound is treated with a dilute aqueous mineral acid such as a 10% solution of an acid such as hydrochloric acid or sulfuric acid to effect hydrolysis and de-protection of the hydroxyl group. This reaction step is also essentially conventional, and suitable reagents, solvents and process conditions may be determined by reference to the above-cited Advanced Organic Chemistry and by routine optimization of reaction parameters.
The protected hydroxyl group may be hydrolyzed and de-protected either before or after the thiophenol group is formed. If the protected hydroxyl group is hydrolyzed first, then the resulting compound has the structure of Formula II, in which R is as described above with respect to Formula II, Pg is H and X is selected from SMgF, SMgCl, SMgBr and SMgI. If the thiophenol is formed first, then the resulting compound has the structure of Formula II in which R and Pg are as described above with respect to Formula II and X is SH. For either compound, when R is a phenyl or alkylphenyl group, the compound of Formula II is an intermediate compound of Formula I in which X is SH and Y and n are as described above for Formula I. Y again represents the groups with which the aryl and aralkyl R groups of Formula II may be substituted.
If the protecting group species that is formed by de-protection of the protecting group is not inert toward thiol groups, then the protecting group species should be removed from the reaction mixture before it reacts with the newly formed thiol group. The species that forms can be removed by essentially conventional techniques, including distillation, extraction with water or reaction with a stronger nucleophile than the thiol group. In fact, the hydroxyl group can be de-protected before the thiophenol group is formed when a nucleophile is added that is strong enough to react preferentially with the de-protected species over the newly-formed thiol group, thereby consuming the species that form upon de-protection.
Following the treatment with the dilute acid, Step III continues with the treatment of the organic layer with a reducing agent such as a mixture of sodium metabisulfite and KOH, a mixture of a metal (such as Zn, Fe or Sn) and H+ or metal hydrides, such as NaBH4 or LiAlH4, at an elevated temperature up to the reflux temperature to reduce any di- and polysulfide species that have formed. Acidification of the aqueous layer with a concentrated mineral acid such as hydrochloric acid or sulfuric acid is performed if a basic reducing agent is employed. Th desired product is thus obtained, which is extracted into an organic solvent such as toluene, diethyl ether, isopropyl ether, methyl tertbutyl ether or halogenated solvents such as dichloromethane or chloroform. These steps are also essentially conventional, and suitable reagents, solvents and process conditions may be determined by reference to the above-cited Advanced Organic Chemistry or through routine optimization of reaction parameters. When R of Formula II is phenyl, the product is a hydroxythiophenol.